Signals produced by a few cells within a single tissue can regulate lifespan and functional aging throughout an animal. These signaling molecules may exert nonautonomous effects at target tissues to induce their protective mechanisms against age-dependent degeneration. Conversely, nonautonomous signals such as insulin/IGF-like hormones may promote somatic functions that favor growth and reproduction, but while being permissive to somatic degeneration. While nonautonomous signaling in aging regulation has been best characterized in terms of centrally produced hormones, and more recently with cytokines and SASP, provocative data from several model systems suggest there are critical, nonautonomous regulators of aging yet to be described. Accordingly, this proposal focuses on small neuropeptide like molecules secreted from specialized cells of the intestine ? gut peptides. Enteroendocrine cells of animal guts, including those of Drosophila and humans, produce many gut peptides that have system-wide impacts on behavior, digestion and metabolism. Working with Drosophila, we propose that gut peptides can also affect lifespan and somatic functional aging by nonautonomous signaling across the organism. In Drosophila, gut peptide production appears change with age, some increasing and others decreasing. We also found that depleting a nutrient sensitive transcription factor in fly enteroendocrine cells was sufficient to block longevity extension by dietary restriction, while inducing this factor appears to increase the ability of dietary restriction to slow aging. We propose that gut peptides secreted from these cells provides a mechanism to regulate aging and in particular in response to diet. The work has three objectives. First is to fully characterize changes in the secretion of gut peptides from fly intestines with age and in response to dietary restriction, and to assay their transcriptional controls. From our identified age-dynamic gut peptides, we will use genetic manipulations to robustly infer which gut have the capacity to nonautonomously control life span and functional aging at target tissues. The second goal is to determine if gut peptides modulate aging through direct signaling at target tissues, and notably through G-Protein Coupled Receptors at these tissues. The third aim explores if gut peptides nonautonomously modulate aging by affecting production of a secondary, relay hormone, such as insulin/IGF or juvenile hormone, which in turn control systemic functional aging. Together these aims will describe a novel tissue function for the intestine in aging control through systemic signaling, and provide a model to explore these highly conserved gut peptides in mammals during aging and in response to dietary restriction.